Histoplasma capsulatum (Hc) is a dimorphic fungal pathogen of worldwide importance that causes a broad spectrum of disease activity. Although the course of infection is mild in most immunocompetent individuals, Hc may produce progressive disseminated infections in individuals immunocompromised by hematological malignancies, cytotoxic therapy, or in individuals with acquired immunodeficiency syndrome (AIDS). Infection with Hc is acquired by inhalation of microconidia or small mycelial fragments into pulmonary alveoli. Inhaled conidia convert into the pathogenic yeast phase within an unknown time frame. Hc yeasts are phagocytized by alveolar macrophages (AM), within which they multiply. Presumably, the dividing yeasts destroy the AM, and subsequently are ingested by other resident AM and by neutrophils (PMN) and macrophages (Mo) recruited to the loci of infection. Repetition of this cycle results in dissemination of Hc via blood and lymphatics. Maturation of specific cell-mediated immunity (CMI) against Hc activates Mo to halt yeast proliferation with gradual resolution of the disease process in most immunocompetent hosts. The overall goal of our research is to understand the biology and biochemistry of the interactions of Hc yeasts and microconidia with human monocyte/Mo and PMN. The major objectives of this proposal are: 1), to define the role of extracellular matrix (EM) proteins and cytokines in activation Mo anti-Histoplasma activity; and 2), to identify the constituents of azurophil granules that mediate PMN fungistatic activity, to define the in vivo role of PMN in host defense against Hc, and to define the interaction between PMN and Mo in mediating host defense against Hc yeast, and their regulation by EM proteins and/or cytokines. The results of these studies should provide significant insight into the pathogenesis of histoplasmosis and aid in the design of new drugs for treatment.